Dopamine is an essential neurotransmitter of the central nervous system. The activity of dopamine is mediated via the binding to five different dopamine receptors. These receptors can be arranged by their morphology and their manner of signal transduction into classes “D1-like” (D1 and D5) as well as “D2-like” (D2, D3 and D4 receptors).
The D3 receptor was first cloned by Sokoloff (Nature 347, 1990, 146) and is especially expressed in the limbic system, in which emotional and cognitive processes are controlled. It is also somewhat less pronounced in the striatal motor tissue where it serves the purpose of fine regulation of movement processes (Joyce, Pharmacol. Ther. 90, 2001, 231-259). Recently the D3 receptor has been considered as a promising target for the development of active agents for the treatment of different psychiatric and motor diseases.
Consequently, D3 agonists could represent valuable therapeutics for the treatment of different types of depression, anxiety disorders, sexual dysfunctions, glaucoma, cognitive disorders, restless leg syndrome, attention deficit hyperactivity syndrome (ADHS), hyperprolactinemia, hyperprolactinoma, eating disorders, Parkinson-associated movement disorders, dopa- and neuroleptic-induced movement disorders, e.g., akathisia, rigor, dystonia and dyskinesia, as well as cocaine, alcohol, opiate and nicotine addiction, galactorrhea and acromegaly.
Further, D3 agonists have neuroprotective potential for the treatment and prophylaxis of neurodegenerative disorders (Pulvirenti et al., Trends Pharmacol. Sci. 23, 2002, 151-153; Joyce, Pharmacol. Ther. 90, 2001, 231-259; EP 0 988 296; WO 03/29233; WO 93/23035).
Thus, there is a need for high affinity D3 agonists with preferably greater functional selectivity as compared to “D1-like” receptors and with significant selectivity as compared to the remaining “D2-like” receptors.
It was surprisingly found that (S)-2-N-propylamino-5-hydroxytetralin has the desired characteristics.
Racemic 2-N-propylamino-5-hydroxytetralin is known from the literature.
Hacksell et al (J. Med. Chem. 22, 1979, 1469) evaluated different N-alkylated 2-aminotetralins in regard to their dopamine receptor stimulating activity. A particular dopaminergic activity was demonstrated for the racemic 2-N-propylamino-5-hydroxytetralin. However, the agonistic activity of the substance with an ED50 of 40 nM/kg is only moderate and the AUC and the half life are short in comparison to the other evaluated compounds. It was found that aminotetralins with N,N-dialkylation were the most active and appropriate compounds for the intended oral administration.
Beaulieu et al. (Eur. J. Pharmacol. 105, 1984, 15) evaluated N,N-disubstituted 2-aminotetralin in regard to its D2 stimulating activity. The racemic 2-N-propylamino-5-hydroxytetralin demonstrated a moderate activity while N,N-dialkylated 2-amino-5-hydroxy derivate, like N-0437 (racemic rotigotine), showed a significantly higher activity. Conclusions to possible therapeutic potential of 2-N-propylamino-5-hydroxytetralin were not made.
Seiler et al. (J. Med. Chem. 29, 1986, 912) disclose 2-N-propylamino-5-hydroxytetralin as an educt for syntheses of N-dialkylated compounds. A biological activity of 2-N-propylamino-5-hydroxytetralin is not described.
Swart et al. (Toxicology Methods 3, 1993, 279) describe the racemate of 2-N-propylamino-5-hydroxytetralin as rotigotine metabolite with weaker dopaminergic activity. Rotigotine (5,6,7,8-tetrahydro-6-[propyl[2-(2-thienyl)ethyl]amino-1-naphthalenol) is an example of a dopamine receptor agonist with D2/D3 agonistic activity. In comparison to rotigotine, which binds with a Kd value of 5 nM to a dopamine receptor rich membrane fraction, 2-N-propylamino-5-hydroxytetralin demonstrates a clearly higher Kd value of 1.3 μM. The authors come to the conclusion that the N-dealkylated metabolites of rotigotine have a dopaminergic activity too weak for them to have a therapeutic relevance.
Swart et al. (J. Analytical Toxicology 18, 1994, 71) disclose the (S)-enantiomer of 2-N-propylamino-5-hydroxytetralin as a metabolite of rotigotine. A biological activity is not described.
Sonesson et al. (J. Med. Chem. 38, 1995, 1319) evaluated the biological activity of monopropyl analogue of {[(trifluoromethyl)sulfonyl]oxy}-2-aminotetralins. The enantiomers of 2-N-propylamino-5-hydroxytetralin were disclosed as intermediate synthesis products, however they were not biologically characterized.
EP 0 026 848, EP 0 717 620, WO 94/26703 and WO 01/38321 disclose 2-N-propylamino-5-hydroxytetralin as an educt for the synthesis of N-dialkylated and sulfonated aminotetralin. The medical application of 2-N-propylamino-5-hydroxytetralin is not suggested.
Van Vliet et al. (J. Med. Chem. 39, 1996, 4233) evaluate the applicability of competition tests with D2L agonists and D2L antagonists for the prediction of dopamine receptor subtype selectivity. Here aminotetralin is evaluated in regard to its D3 selectivity and potential suitability as antipsychotic. Within the scope of this evaluation, racemic 2-N-propylamino-5-hydroxytetralin was applied as well as 27 other substances. Functional data for (ant)agonistic activity of the used substances was not collected. The medical use of 2-N-propylamino-5-hydroxytetralin is not suggested. On the other hand, the authors come to the conclusion on p. 4236 that, with the exception of compound (+)25, none of the applied substances demonstrate the desired pharmacological profile of a D3 selective antipsychotic.
In summary, the racemic 2-N-propylamino-5-hydroxytetralin is, from the state of the art, known as an unselective, moderately active dopamine agonist with a modest half life. Even though a known dopaminergic activity of the racemic 2-N-propylamino-5-hydroxytetralin has been known since 1969 (see Hacksell et al., supra), a medical use of this substance is not described and is also not suggested. On the contrary, Swart et al. come to the conclusion that the N-dealkylated metabolites of rotigotine have a dopaminergic activity which is too weak to be therapeutically relevant (Tox. Meth. 3, 1993, p. 289, last paragraph).